Key-words:
Delayed cerebral ischemia - outcome - subarachnoid hemorrhage
Introduction
The worldwide incidence of subarachnoid hemorrhage (SAH) is 9.1/100,000 population
with higher incidences in Finland and Japan.[[1]]
Initial hemorrhage, early rebleeding, and delayed cerebral ischemia (DCI) lead to
high mortality and morbidity rates in patients with ruptured cerebral aneurysms. The
30-day mortality may be 40%–45%.[[2]] The timing to treatment remains controversial, but the general consensus is that
early treatment (<3 days after SAH) is preferred.[[3]] Because aneurysm rebleeding significantly affects morbidity and mortality, most
neurovascular surgeons aim to treat the aneurysm as early as possible. However, aneurysm
treatment may be delayed due to reasons which are difficult to avoid. Symptomatic
cerebral vasospasm before aneurysm treatment may also complicate treatment.[[4]] There is no standard guideline outlining patient management before definite treatment
of the aneurysm. In-hospital management varies, but there is no established protocol
for optimizing the patient's condition while waiting for definite treatment or for
improving their long-term outcome.
Thus, we compared the incidences of in-hospital rebleeding and long-term outcomes
before and after implementation of our protocol in preventing rebleeding.
Methodology
Patient populations
All patients were treated at a single center with a high case volume (more than 70
ruptured aneurysm cases per year) by experienced neurosurgeons and neuro-interventionists.
The study period was from 2013 to 2015. Two hundred and eight patients presented during
this period with definite SAH proven by computed tomography (CT) or lumbar puncture.
The intracranial aneurysm was confirmed with cerebral angiography or CT angiography
(CTA). Patients were excluded if they had aneurysms related to arteriovenous malformation,
infectious aneurysm, or traumatic aneurysm.
Prior to July 1, 2014, treatment for aneurysmal SAH at our institution varied depending
on the neurosurgeon overseeing the patient. These treatments included blood pressure
control, antifibrinolytic agents, and ventriculostomy care. However, after July 2014,
a protocol to prevent rebleeding was implemented. We named this the “REST protocol.”
R stands for absolute bed rest, adequate pain control, minimizing stimuli, and use
of laxatives; E stands for euvolemic hydration status;[[5]] S stands for systolic blood pressure (SBP) control, <160 mmHg prior to definite
treatment and within the range of 140–180 mmHg after treatment; and T stands for the
earliest possible treatment [[6]] and intravenous tranxemic injection in patients with an expected delay in treatment
of more than 72 h.[[7]] For patients with intracranial pressure >20 cmH2O who required ventriculostomy,
we avoided transmural pressure reduction.[[8]] In patients with intracranial hypertension for whom CTA did not provide sufficient
information for definite treatment, ventriculostomy for hydrocephalus or blood clot
removal for large intracerebral hematoma was performed, without treating the aneurysm.
We collected the following data from all participants: age, sex, history of smoking
and hypertension, WFNS grade, Hunt and Hess grading, Fisher grading, preoperative
hydrocephalus, aneurysm location, size, number, timing of clipping or coiling, in-hospital
rebleeding, postoperative complications during hospitalization such as DCI, medical
complications, and discharge outcomes. WFNS grading was divided into good grade WNFS
1–3 and poor grade WFNS 4–5.
Aneurysm rebleeding was defined as new bleeding, as shown in the CT scan. We defined
DCI as the presence of focal neurological deficits or decrease on the Glasgow Coma
Scale of at least two points. Those neurological deficits should be absent immediately
after aneurysm occlusion and should not be due to other causes such as rebleeding,
acute or worsening hydrocephalus, electrolyte disturbance, or seizure.[[9]] Hydrocephalus was defined as ventricular dilatation with enlarged temporal horns
(>2 mm wide) on a CT scan. The surgical-related complications included ventriculostomy,
ventriculoperitoneal shunt, decompressive craniectomy or lobectomy, and tracheostomy.
Medical complications included pneumonia, pulmonary edema, myocardial complication,
and meningitis.
The main outcome was assessed using the modified Rankin Scale (mRS) at 6 and 12 months.
This outcome was classified as being either favorable (mRS 0–3) or unfavorable (mRS
4–6). Continuous data were presented as mean ± standard deviation and categorical
data as number (percentage). An independent sample t-test was performed for continuous
variables. A Chi-square test or Fisher's test was used for categorical variables.
The odds ratio (OR) and 95% confidence interval (CI) were calculated. P < 0.05 was
considered statistically significant. Survival in both cohorts was analyzed, and Kaplan–Meier
survival estimates were used to evaluate the differential effect of the preventive
rebleeding protocol. Subgroup analysis of WFNS good grade (1–3) and poor grade (4–5)
at presentation survival for survival was also estimated. Wilcoxon testing was used
to compare survival estimates to determine the equality of the survival curves. The
protocol of the present study was approved by the Ethics Committee of Khon Kaen University,
according to the standards laid out in the Helsinki Declaration.
Results
One hundred and four patients were treated before the implementation of the protocol
and another 104 patients were treated thereafter.
Baseline characteristics
We identified 208 patients with ruptured cerebral aneurysm from 2013 to 2015. One
hundred and four patients were treated before the protocol implementation, and 104
patients were treated thereafter. Baseline characteristics and coexisting conditions
are shown in [[Table 1]]. In the preprotocol cohort, 56.73% of patients were women, 46.1% had elevated SBP
prior to surgery, 28.8% had poor grade WFNS 4–5, 87.5% had Fisher's grade 3–4, and
85.6% had an anterior circulation aneurysm. The average age in this group was 55.48
± 12.7, and average aneurysm size was 5.9 ± 3.5 mm. Nearly 85.6% of the patients in
this group underwent surgical treatment, 8.6% underwent endovascular treatment, and
5.8% underwent conservative treatment. There were no significant differences in terms
of baseline characteristics between the two cohorts, with two exceptions. Hydrocephalus
was lower in the postprotocol group than in the preprotocol group (32.7% vs. 53.8%;
P = 0.002), and a higher proportion of patients underwent conservative treatment in
the postprotocol than in the preprotocol group (16.3% vs. 5.8%; P = 0.015).
Table 1: General characteristics
Perioperative outcomes
Time to definite aneurysm treatment
During the preprotocol period, definite aneurysm treatment was initiated at a median
interquartile range of 95.5 (55–154) h from the onset of symptoms of SAH; 66.3% of
patients underwent delayed definite treatment after 72 h. In the postprotocol period,
time to definite aneurysm was at a median interquartile range of 82.0 (53–226) h from
the onset of symptoms. Nearly 57.9% had delayed definite treatment after 72 h, as
shown in [[Table 2]].
Table 2: Perioperative outcomes of patients pre/post implementation of the preventive rebleeding
protocol
Comparison of in-hospital rebleeding and complications
The incidence of in-hospital rebleeding before definite treatment was 6.7% (7/104),
as in [[Table 2]], during the preprotocol period and 2.8% (3/104; OR 0.4, 95% CI = 0.10–1.63, P =
0.20) during the postprotocol period. In the postprotocol cohort, 7.7% had DCI versus
44.2% in the preprotocol cohort (OR = 0.10, 95% CI = 0.04–0.23, P < 0.001).
The postprotocol cohort had lower rates of perioperative medical and surgical complications
(e.g., pneumonia; 26.9% vs. 36.5%; OR = 0.63, 95% CI = 0.35–1.15, P = 0.13) and had
shorter hospital stays (median of 8 days vs. 11 days, P = 0.09).
Proportion of unfavorable outcomes and 180-day mortality
During the preprotocol period, 33 of 104 (32.7%) patients had unfavorable outcomes
(mRS 4–6) at 1 year compared with 28 of 104 (26.9%) in the postprotocol period. The
OR of unfavorable outcome postprotocol was 0.74 (95% CI = 0.41–1.35, P = 0.33). There
was no significant difference in 180-day mortality between the two cohorts (14.4%
preprotocol vs. 13.5% postprotocol).
Subgroup analysis was performed according to WFNS grading. The good grade was defined
in WNFS grade 1–3 and poor WFNS grade 4–5. Good-grade patients treated using the new
protocol had slightly lower in-hospital rebleeding rates (2.8% vs. 6.7%; OR = 0.4,
95% CI = 0.07–2.16, P = 0.29) experienced significantly lower rates of DCI (4.3% vs.
40.5%, OR = 0.06, 95% CI = 0.01–0.22, P < 0.001) and had a lower proportion of unfavorable
outcomes at 1 year (mRS 4–6; 12.8% vs. 27.0%; OR = 0.40, 95% CI = 0.17–0.95, P = 0.03),
as in [[Table 3]]. Poor-grade patients in the postprotocol group also had significantly lower rates
of DCI (14.7% vs. 53.3%, OR = 0.15, 95% CI = 0.04–0.49, P < 0.001). However, the differences
in rebleeding incidence and clinical outcomes did not reach statistical significance.
Table 3: Comparison of clinical outcomes, according to subgroup analysis
Mortality among patients' WFNS scores of 1–3 at 1 month after preventive implementation
of the rebleeding protocol decreased from 10.8% to 5.7% (P = 0.57), and mortality
at 6 months decreased from 16.3% to 8.8% (P = 0.68). After implementation of the preventive
rebleeding protocol, mortality at 1 month in patients with WFNS scores of 4–6 increased
from 13.8% to 17.8% (P = 0.63), but mortality at 6 months decreased from 27.6% to
23.5% (P = 0.98). The survival curves were shown in [[Figure 1]].
Figure 1: Survival after implementation of the preventive rebleeding protocol in patients with
WFNS scores of 1-3 and 4-5
Discussion
Rebleeding has been recognized as a leading preventable cause of death and disability
after aneurysmal SAH and is associated with higher rates of complications. The mortality
associated with rebleeding has been reported to be as high as 70%.[[10]] The optimal timing of ruptured intracranial aneurysm treatment remains controversial,
but the general consensus tends to favor early treatment (<3 days after SAH). However,
a previous study found that, despite early treatment, the rebleeding incidence is
still 5.7%.[[11]] In this study, the incidence of rebleeding in the preprotocol period was 6.7% compared
to 2.8% in the postprotocol period. Delayed patient referral is a common problem due
to the difficulty of SAH diagnosis, lack of interhospital communication, delayed vascular
study, and avoidance of suboptimal condition for aneurysm obliteration at night.[[12]] Aneurysm treatment was delayed more than 72 h in 66.3% and 57.9% of cases in the
preprotocol period and postprotocol period, respectively. If early aneurysm obliteration
is not possible, the patients' blood pressure should be strictly controlled (<160
mmHg), and they should undergo a short course of antifibrinolytic agents. These patients
should also be given stool softeners, bed rest, and analgesia (e.g., morphine sulfate)
to diminish hemodynamic fluctuations. There is controversy with regard to the optimal
therapy for hypertension in SAH patients.[[13]] Although decreasing SBP to < 160 mmHg is reasonable,[[7]] the benefits gained from this may be offset by increased risk of infarction. In
one report, control of diastolic blood pressure (<100 mmHg) led to a lower incidence
of rebleeding but a higher incidence of infarction.[[14]]
DCI is one of the leading causes of morbidity and mortality in patients with SAH.
Up to one-third of these patients with developing DCI, but aggressive vasospasm treatment,
can only be pursued after the aneurysm has been secured. Previous systematic reviews
examining triple-H therapy for vasospasm prophylaxis have found no strong evidence
to support this.[[15]] More recently, the focus has shifted toward maintenance of euvolemia with the crystalloid
or colloid solution and induced hypertension with vasopressor agents such as phenylephrine,
norepinephrine, or dopamine.[[16]]
However, during the postprotocol period in this study, this present strictly in euvolemic,
nimodipine oral form and SBP <160 mmHg for in-hospital rebleeding prevention but immediate
postoperative period, this protocol tries to drive SBP with hypervolemia first and
stepwise with vasopressor keep SBP 140–180 mmHg due to more than half of the patients
in this study were secured aneurysm in vasospasm period and transcranial doppler was
not available. Our study found a DCI reduction from 44.2% to 7.7% (P < 0.001). The
effect size is important and relatively large (OR 0.10, 95% CI = 0.04–0.23, P < 0.001)
compared with that in a previous study.[[17]]
To reduce the occurrence of unfavorable outcomes (mRS 4–6) in patients with ruptured
cerebral aneurysm, some neurovascular surgeons implemented urgent treatment within
24 h [[18]] including direct referral on acute presentation, early vascular study, aneurysm
treatment, and emergency protocol. These steps were able to significantly reduce the
incidence of in-hospital rebleeding to 2.1% and lower the proportion of patients with
unfavorable clinical outcomes at 1 month (mRS4-6) from 20.3% to 12.1% (P = 0.008).
For several reasons effect to delayed aneurysm obliteration then protocol was implemented.
This study showed a significant reduction in unfavorable outcomes at 12 months (OR
0.4, 95% CI = 0.17–0.95, P = 0.03) in patients with WFNS grades of 1–3 in terms of
a reduction in hospital rebleeding, DCI, and 30- and 180-day mortality rates. However,
changes in terms of clinical outcome did not reach statistical significance in patients
with poor WFNS because of higher proportions of whom had poor WFNS grades and underwent
conservative treatment during the postprotocol period.
This study has several limitations. First, it was a retrospective analysis from a
single institute and compared data from different time periods, making it difficult
to avoid selection bias. Second, almost all patients were transferred from another
hospital after 24 h, which might affect the incidence of rebleeding. Third, patients
with poor WFNS grades often present with coma, making it difficult to identify DCI
which may have led to an underestimated incidence of DCI.[[19]] Finally, some factors that may have impacted outcomes may not have been identified
such as surgeon experience, aneurysm complexity, perioperative blood testing, and
complication.
Conclusion
The preventive rebleeding protocol significantly reduced unfavorable outcomes in patients
with ruptured aneurysm by reducing in-hospital rebleeding, DCI, and medical complications,
especially in patients with good WFNS grades.
